Cancer has become a serious threat to human health. Researchers are pursuing effective, safe, and low-toxicity small molecular anti-tumor drugs. With the development of medicinal chemistry, research on natural products with anti-tumor activities and the derivatives of these products became an important trend.
Cancer has become a serious threat to human health. It is essentially a genetic disease. Various environmental and genetic carcinogenic factors cause DNA damage in a synergistic or sequential manner, thereby activating proto-oncogenes and/or inactivating tumor suppressor genes, changing in apoptosis-regulating genes and/or DNA repair genes, and then causing abnormal expression level and the transformation of target cells. The transformed cells first have mostly clonal hyperplasia, and through a long multi-stage evolution process, one clone relatively unrestrictedly amplifies and selectively form subclones with different characteristics (heterogeneity), obtaining the ability to infiltrate and transfer (malignant transformation), and forming malignant tumors, mainly due to unreasonable diet, genetic factors, and environmental factors. The mechanism of action for antitumor drugs and the target of the drugs vary. Because tumor cells are prone to multidrug resistance, treatment often fails. Researchers are diligently and continuously searching for effective and safe anti-tumor drugs.
Hesperetin is a class of natural flavonoid compounds isolated from citrus genus. It has anti-inflammatory, anti-oxidation, anti-allergic reaction, cardiovascular and anti-tumor activities. Hesperetin is mainly derived from the hydrolysis of hesperidin, and its glycosides can hydrolyzed by human intestinal microbial. Hesperetin is the main active ingredient of the herbs Chenpi, Qingpi, Citrus aurantium. Studies have shown that hesperetin could reduce the toxicity of doxorubicin in rats. Hesperetin also has anti-tumor activities. Studies have shown that hesperetin can inhibit the proliferation of HepG2 cells in vitro, and there is a time-dependent and dose-effect relationship. The mechanism of hesperetin's inhibition of the growth of hepatocellular carcinoma cells may be that apoptosis is promoted by inducing G2 arrest and upregulation of Caspase-3 protein expression.
Hesperetin is widely available and has no side effects and unique biological activities. The synthesis and structural modification of hesperetin has become popular in the development of new drugs. Cinnamic acid, aza-cinnamic acid and their derivatives have antitumor activities. As one new drug research and development strategy, they can be used as lead compounds for further research to obtain candidate compounds with better efficacy. One example is histone deacetylase inhibitor (HDI) inhibitor, Chidamide (approved in 2014), which was inspired by the introduction of aza-cinnamic acid and its derivatives in the compound design.
There remains a need for effective and safe small molecular anti-tumor drugs. There is also no report of hesperetin aza-cinnamic acid derivatives.